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By Jill Horn

“The keto diet has successfully been applied in the treatment of treatment-resistant seizures, type 1 and type 2 diabetes, and metabolic syndrome.”

The ketogenic diet (“keto diet”) has recently received increased attention from the general public as well as the scientific community.¹ The proposed benefits include weight loss, improved metabolic regulation, reduced systemic immune activation (“metabolic endotoxemia”), and improved cardiovascular health.² The diet has successfully been applied in the treatment of treatment-resistant seizures, type 1 and type 2 diabetes, and metabolic syndrome, while its use in the treatment of cancer, autism spectrum disorder, and Alzheimer’s disease is currently not based on solid scientific evidence.³ Problems that limit the practicality of this diet as a long-term treatment include compliance, difficulties with implementation, and adverse side effects.³

“The brain can utilize ketone bodies as its primary energy source.”

The keto diet is characterized by very low carbohydrate intake, low to moderate protein, and high consumption of fat (usually from animal sources), with fat making up 70% of the caloric intake.¹ The diet is designed to provide sufficient protein for growth but an insufficient quantity of carbohydrate, so that the metabolic needs of the body need to be met through a way other than glucose, the breakdown product of carbohydrates, namely ketosis. Therefore, in the ketogenic diet energy is mainly derived from fatty acid oxidation, which takes place in the mitochondria. The synthesis of ketone bodies happens primarily in the liver, from where they are then transported to the periphery and the brain. In normal conditions, the brain’s primary fuel is glucose, but at a high degree of ketosis in the body due to lack of glucose, the brain can utilize ketone bodies as its primary energy source. The ketogenic diet therefore mimics the fasting state, which is why it has been used successfully in the treatment of epilepsy and a small number of metabolic diseases related to obesity.⁴

“The gut microbiota are both necessary and sufficient for seizure protection.”

The underlying mechanisms of the ketogenic diet’s proposed effect on neuroprotection require further investigation.⁵ Some forms of epilepsy have been associated with autoimmune disorders, and specific autoantibodies have been identified in certain seizure disorders.⁶ Like with other autoimmune disorders, a link with alterations in the gut microbiome has been suggested and several studies have demonstrated effects of a ketogenic diet on the gut microbiome and its role in treating epilepsy.⁵ The gut microbiota modulates several neurological, immunological, and metabolic pathways, and thus it was hypothesized to be the underlying mechanism in the ketogenic diet’s positive effect on seizure prevention.³ In the adult, the composition and function of the gut microbiota are predominantly shaped by diet, hence the successful treatment of various conditions through dietary therapy is based on a health-promoting alteration of the gut microbiome.⁵ A recent study in a mouse model of epilepsy by Olson et al. showed that the gut microbiota is both necessary and sufficient for seizure protection.³ In this study, the ketogenic diet was correlated with an increase in A. muciniphila and Parabacteroides, both of which are bacteria taxa required for mediating anti-seizure effects and also have been observed to increase in the fasting state.³ Moreover, an increase in microbial GABA production was observed on the ketogenic diet providing a plausible mechanism mediating the diet related antiseizure effect.³

While the ketogenic diet may be a promising approach in the treatment of refractory seizures, it also has been observed to negatively affect certain beneficial bacteria taxa in healthy subjects. For example, a recent UCSF study in mice showed that specifically the relative abundance of Bifidobacteria decreased drastically in the ketogenic diet.² Bifodobacteria species are thought to be of critical importance to the maintenance of human health, mainly because of their release of various health-promoting metabolites.⁷ Furthermore, the altered microbial composition in mice adhering to ketogenic diets triggered a reduction in the amount of Th17 immune cells, which are critical in fighting off infectious disease.²

“The keto diet is depriving the gut microbes of a steady supply of complex carbohydrates and fiber, which leads to compromised gut microbial health.”

Even though the ketogenic diet has been shown to be beneficial in the treatment of refractory seizures, and in normalizing the obesity related metabolic disturbances, including type 1 or type 2 diabetes.¹ This diet is depriving the gut microbes of a steady supply of complex carbohydrates and fiber, which leads to compromised gut microbial health. The gut microbiota primarily utilizes dietary fiber for energy and sustenance, which is why a diet very different from the keto diet, one that includes a high intake of fiber in form of whole grains, legumes, vegetables, and fruit is recommended for long-term health promotion.⁵

In summary, therapeutic time-limited use of the ketogenic diet in the treatment of a small number of specific diseases is suggested, while long-term application of this diet should be discouraged both in healthy individuals and patients. The lack of complex carbohydrates and a variety of plant-based fiber combined with a high intake of saturated fat largely from animal sources is likely to have major negative effects on the diversity and richness of the gut microbiome and on overall health in the long run

References

1. Ludwig D. S. (2020). The Ketogenic Diet: Evidence for Optimism but High-Quality Research Needed. The Journal of nutrition, 150(6), 1354–1359.
2. Weiler, N. (2020). Ketogenic Diets Alter Gut Microbiome in Humans, Mice. University of California, San Francisco.
3. Olson, C. A., Vuong, H. E., Yano, J. M., Liang, Q. Y., Nusbaum, D. J., & Hsiao, E. Y. (2018). The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell, 173(7), 1728–1741.e13.
4. Hartman, A. L., Gasior, M., Vining, E. P., & Rogawski, M. A. (2007). The neuropharmacology of the ketogenic diet. Pediatric neurology, 36(5), 281–292.
5. Fan, Y., Wang, H., Liu, X., Zhang, J., & Liu, G. (2019). Crosstalk between the Ketogenic Diet and Epilepsy: From the Perspective of Gut Microbiota. Mediators of inflammation, 2019, 8373060.
6. Ong, M. S., Kohane, I. S., Cai, T., Gorman, M. P., & Mandl, K. D. (2014). Population-level evidence for an autoimmune etiology of epilepsy. JAMA neurology, 71(5), 569–574.
7. Arboleya, S., Watkins, C., Stanton, C., & Ross, R. P. (2016). Gut Bifidobacteria Populations in Human Health and Aging. Frontiers in microbiology, 7, 1204.

Jill Horn is a recent UCLA graduate with a degree in Neuroscience. She is deeply interested in the interconnectedness of body, mind, and spirit takes an integrative approach to health and well-being.